The field of this invention encompasses the treatment of syndromes which result from an inadequate blood perfusion of vital tissues and evolves in a general stimulant effect of drugs which improve cardiovascular efficiency, often accompanied by behavioral arousal, as well. A more specific aspect of this invention relates to therapy of circulatory shock which is defined as: "The clinical manifestations of an inadequate volume of circulating blood accompanied by physiologic adjustments of the organism to the progressive discrepancy between the capacity of the arterial tree and the volume of blood to fill it" (Blakiston's New Gould Medical Dictionary, 2nd edt., p. 1092, McGraw-Hill, New York, 1956.)
At present, circulatory shock is clinically treated by the administration of fluids such as blood, plasma, volume expanders, or Ringer's lacatate in conjunction with direct-acting cardiovascular drugs such as "Dopamine" which have vasoactive as well as cardiogenic effects. Such therapeutic approach is often ineffective in reversing various forms of shock. Moreover, serious drawbacks limit the clinical utility of such therapeutic regimens. For example, blood typing or intravenous-system setup necessitate a clinical environment which can result in potentially fatal delays between diagnosis and treatment.
Recent pre-clinical experimentation by this inventor has revealed that the body's own opiates, collectively referred to as "endorphins," appear to contribute substantially to the loss of cardiovascular function and resulting shock stress associated with infections, hemorrhage, and spinal-cord injuries. Opiate (narcotic) receptor antagonists are available which pharmacologically oppose endorphin's effects in exacerbating the severity of shock. The therapeutic use of opiate antagonists in treating shock is the subject of a pending patent "Narcotic Antagonists in the Therapy of Shock," Ser. No. 003,699, filed Jan. 16, 1979 by John W. Holaday and Alan I. Faden. Experiments describing the use of one specific opiate antagonist, "Naloxane," are disclosed therein.
Although naloxone is an extremely safe drug with little or no toxic effect, this opiate antagonist also blocks or reverses the analgesic effects of the body's own opiates. Thus, receptor-level opiate antagonists like naloxone may have the adverse effect of intensifying post-traumatic pain by inhibiting endorphin-medicated analgesia even as they improve the shock state and ultimate survival. A drug which reverses shock without affecting an increase in the perception of pain would have obvious advantages.
The use of thyrotropin releasing hormone (TRH) in the therapy of circulatory shock, as disclosed herein, provides a distinctly different approach to this problem. It has been shown that thyrotropin releasing hormone has no effect upon pain perception or opiate-induced analgesia. Thus, TRH and related substances have substantial advantages over existing therapeutic approaches in shock since cardiovascular performance and survival are improved without the potential for enhancing traumatic pain. The absence of any effect of TRH upon opiate analgesia, combined with the opposing behavioral and physiological effects of TRH and opiates, allows for the concurrent administration of opiates, such as morphine and TRH. This would result in the presence of pain relief without the manifestation of the adverse physiological and behavioral side effect of opiates.
Experimental evidence also indicates an arousing or stimulant effect of TRH. When the nervous system is deprived of appropriate blood flow and oxygen, such as may occur following a stroke or myocardial infarction, irreversible nerve cell death may result. The therapeutic administration of TRH to experimental animals subjected to central nervious system (CNS) ischemia results in an improvement in behavioral and physiological parameters. This suggests the potential for TRH and related analogs to minimize neurologic deficits following CNS ischemia such as stroke. Moreover, TRH appears to function as a behavioral stimulant which may improve performance and oppose fatigue.